Effect of deuteration on the metabolism and clearance of some pharmacologically active compounds-synthesis and in vitro metabolism of deuterated derivatives of dronedadrone

The synthesis and in vitro metabolism studies of a family of specifically deuterated derivatives of dronedarone are described. Metabolic stability and clearance of the parent compound are not sensitive to deuterium substitution, irrespective of the position of the heavy label. A series of eight site specifically deuterated analogues of dronedaraone (R1−R5 = H or D) were synthesised and the in vitro metabolic behaviour of each compound investigated using human hepatocyte preparations. Compared to the unlabelled parent compound, no significant differences in metabolic stability and clearance could be detected across the series of derivatives.